CN1617868A - 作为EP2-受体激动剂的ω-环烷基17-杂芳基前列腺素E2 类似物 - Google Patents
作为EP2-受体激动剂的ω-环烷基17-杂芳基前列腺素E2 类似物 Download PDFInfo
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- CN1617868A CN1617868A CNA02826178XA CN02826178A CN1617868A CN 1617868 A CN1617868 A CN 1617868A CN A02826178X A CNA02826178X A CN A02826178XA CN 02826178 A CN02826178 A CN 02826178A CN 1617868 A CN1617868 A CN 1617868A
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- Prior art keywords
- hydroxyl
- compound
- heptan
- chlorothiophene
- olefin
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Abstract
本发明涉及E型前列腺素的衍生物一般说来作为EP2激动剂,具体地说作为降眼压药的应用。根据本发明使用的PGE衍生物用式(I)和式(II)表示:其中影线部分代表一个α键,实心三角形代表一个β键,波纹线部分代表α或β键,虚线代表一个双键或单键,X是选自氢和卤素,R3是杂芳基或取代的杂芳基,R1和R2独立地选自氢或有最多6个碳原子的低级烷基,或有最多6个碳原子的低级酰基,R选自CO2R4、CONR4 2、CONR4 2、CH2OR4、CONR4SO2R4、P(O)(OR4),式中R4选自氢、苯基和1-6个碳原子的低级烷基;n是0或从1到4的整数。
Description
背景技术
本申请是以2001年11月5日提交的美国专利临时申请06/338,838为基础并要求其利益。
技术领域
本发明涉及作为EP2-受体激动剂的ω-环烷基17-杂芳基前列腺素E2类似物。这些化合物是有效的降眼压药,特别适合用于治疗青光眼。
相关技术描述
降眼压药可用于治疗多种高眼压病症,例如手术后和激光小梁切除术后的高眼压发作、青光眼和用作手术前的调节剂。
青光眼是一种以眼内压增高为特征的眼病。根据其病因,青光眼被分成原发性或继发性两类。例如,成人中的原发性青光眼(先天性青光眼)可以是开角型青光眼或者是急性或慢性的闭角型青光眼。继发性青光眼是由已经存在的眼病例如眼色素层类、眼内肿瘤或扩大的白内障等引起的。
原发性青光眼的根本原因尚不清楚。眼球内压增高是由于眼房水流出阻塞造成的。在慢性开角型青光眼中,眼前房及其解剖学结构看似正常,但是眼房水的排出受阻。在急性或慢性闭角型青光眼的情形,眼前房很浅,虹膜角变窄,而且虹膜可能阻塞巩膜静脉窦入口处的小梁网。瞳孔的扩大可能将虹膜根部向前推向该角,并可能造成瞳孔阻滞,从而促成急性发作。具有狭窄的眼前房角的眼睛容易遭受不同严重程度的急性闭角青光眼发作。
继发性青光眼是由对于眼房水从眼后房流入眼前房并随后进入巩膜静脉窦的任何干扰引起的。前房部分的类症可能由于在虹膜膨起中造成虹膜后完全粘连而阻止眼房水流出,并可能用渗出物堵塞排液通道。其它的常见原因是眼内肿瘤,扩大的白内障,视网膜中心静脉阻塞,眼睛创伤,手术操作和眼内出血。
将所有类型都考虑在内,青光眼在年龄超过40岁的人中发病率约为2%,并且可能在迅速丧失视力之前渐近地发展多年。在不需要手术的情形,传统上选择局部给药的β-肾上腺素受体拮抗剂作为治疗青光眼的药物。
已经报道某些类花生酸及其衍生物具有降眼压活性,并被推荐用于青光眼治疗。类花生酸及其衍生物包括多种生物学重要的化合物,例如前列腺素及其衍生物。前列腺素可以描述为具有以下结构式的前列腺烷酸衍生物:
根据结构和在前列腺烷酸主链的脂族环上携带的取代基,已知有各种不同类型的前列腺素。进一步的分类是基于用一般类型前列腺素之后的数字下标表示的侧链中不饱和键的数目[例如前列原素E1(PGE1)、前列腺素E2(PGE2)],和用α或β表示的脂族环上取代基的构型[例如前列腺素F2α(PGF2α)]。
前列腺素早先被认为是有效的升眼压药,然而,在迈十年里积累的证据表明,一些前列腺素是高度有效的降眼压药,并且很理想地适合青光眼的长期药物治疗(例如见,Bito,L.Z.
Biological Protection with Prostaglandins,Cohen,M.M.,ed.,BocaRaton,Fla,CRC Press Inc.,1985,pp.231-252;和Bito,L.Z.,
Applied Pharmacology in the Medical Treatment of Glaucomas Drance,S.M.andNeufeld,A.H.eds.,New York,Grune&Stratton,1984,pp.477-505.)。这些前列腺素包括PGF2α,PGF1α、PGE2和这些化合物的某些脂溶性酯类,例如C1至C2烷基酯,例如1-异丙酯。
虽然准确的机制仍不清楚,但是实验结果表明,前列腺素引起的眼压下降是由于房水葡萄膜巩膜途径的增多造成的[Nilsson等,Invest.Ophtahlmol.Vis.Sci.(suppl),284(1987)]。
PGF2α的异丙酯已显示出比母体化合物大得多的降压效力,这可能是由于它能更有效地穿过角膜。1987年,此化合物被说成是“至今报道的最有效的降眼压药”[例如见,Bito,L.E.,
Arch.Ophthalmol.105,1036(1987),和Siebold等.,
Prodrug52(1989)]。
虽然前列腺素似乎避免了显著的眼内副作用,但在人类于眼部使用这些化合物,特别是使用PGF2α及其前药,例如其1-异丙酯时,总是发生眼表面(结膜)充血和异物敏感性。前列腺素在治疗与眼压升高相关的病症(例如青光眼)方面的临床可能性由于这些副作用而大受限制。
在转让给Allergan;Inc.的一系列共同未决的美国专利申请中,公开了具有增强的降眼压活性,而副作用却没有或大大减小的前列腺素酯类。共同未决的USSN 596,430(1990年10月10日提交),现在的美国专利5,446,041,涉及一些11-酰基前列腺素,例如11-新戊酰基、11-乙酰基、11-异丁酰基、11-戊酰基和11-异戊酰基PGF2α。降低眼球内压的15-酰基前列腺素公开于共同未决的申请USSN 175,476(1993年12月29日提交)。类似地,已知前列腺素的11,15-、9,15-和9,11-二酯,例如11,15-二新戊酰PGF2α具有降眼压活性。参见共同未决的专利申请USSN 385,645(1989年7月7日提交,现在美国专利4,994,274)、584,370(1990年9月18日提交,现在美国专利5,028,624)和585,284(1990年9月18日提交,现在美国专利5,034,413)。所有这些专利申请的公开内容都特意并入本文作为参考。
发明概要
本发明涉及一种治疗高眼压的方法,该方法包括对患有高眼压的哺乳动物施用治疗有效量的式I化合物
其中影线部分代表一个α键,实心的三角形代表一个β键,波纹线部分代表α或β键,虚线代表双键或单键,X是氢或是卤基,例如氟或氯基,R3是杂芳基或被取代的杂芳基,R1和R2独立地选自氢或有最多6个碳原子的低级烷基,或是有最多6个碳原子的低级酰基,R是选自CO2R4、CONR4 2、CH2OR4、CONR4SO2R4、P(O)(OR4)和
其中R4是选自H、苯基和有1-6个碳原子的低级烷基,n是0或从1至4的整数。
在另一方面,本发明涉及一种包装在适合计量使用的容器内的眼用溶液,该溶液含有治疗有效量的式(I)化合物(其中的符号具有以上含义)或其可药用的盐,和与其混合的无毒、可眼用的液体载体。特别是,杂芳基上的取代基可以选自低级烷基,例如C1-C6烷基;OR4;CO2R4;卤素,例如氟、氯和溴;三氟甲基(CF3);COR4,例如COCH3;COCF3;SO2NR4,例如SO2NH2;NO2;CN等。
在又一方面,本发明涉及一种药物产品,其中含有一个适合将其内容物按计量方式分配的容器和容器内的如上定义的一种眼用溶液。
最后,下面公开和按本发明方法使用的以上化学式表示的某些化合物是新颖的非显而易见的。
附图简介
图1是与本发明化合物,例如具体公开于实施例12H和L及13H和L的化合物有关的某些化合物的化学合成示意图。
图2是与本发明化合物,例如具体公开于实施例16H和L及17H和L的化合物有关的某些化合物的化学合成示意图。
发明详述
本发明涉及ω-环烷基17-杂芳基前列腺素E2类似物作为EP2受体激动剂的应用。根据本发明使用的化合物可用以下结构式I概括:
其中各取代基和符号与前面的定义相同。碳原子5和6之间(C-5)和碳原子13和14之间(C-13)的键上的虚线代表一个单键或双键。如果在C-5或C-13处使用两根实线,则表示该双键的一种特殊构型。在C-8、C-9和C-11处使用的影线指示α构型。C-12处的三角形代表β取向。
一组优选的本发明化合物包括具有以下结构式II的化合物:
其中Z是选自O和S,A选自N,-CH和C,R5选自氢、卤素、1至6个碳原子的低级烷基和1-6个碳原子的低级烷氧基,R6和R7是选自氢、卤素、1-6个碳原子的低级烷基和1-6个碳原子的低级烷氧基,或者,R6和R7与以下基团
一起形成一个稠合的芳族环。
另一组优选化合物具有以下化学式III:
在以上化学式中,取代基和符号的定义同上。
本发明的以上化合物可以用本领域已知的方法或按照以下的工作
实施例制备。
以下化合物是本发明化合物的特别优选的代表。
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氯环戊基}庚-5-烯酸甲酯
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氯环戊基}庚-5-烯酸
(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氟环戊基}庚-5-烯酸甲酯
(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氟环戊基}庚-5-烯酸
(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]环戊烯基}庚-5-烯酸甲酯
(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]环戊烯基}庚-5-烯酸
可药用的盐是保留了母体化合物的活性并且在其被服用的意义上对服用对象不产生任何有害或不良影响的任何盐类。特别有价值的是与无机离子例如钠、钾、钙、镁和锌形成的盐。
药物组合物可以通过将作为活性组分的治疗有效量的至少一种本发明化合物或其可药用的酸加成盐与常规的可眼用的药物赋形剂组合来制备,并制备成适合局部给药的眼用单位剂型。在液体制剂中治疗有效量一般为约0.0001-5%(w/v),优选为约0.001-1.0%(w/v)。
对于眼部用药,优选用生理盐水溶液作为主载体制备溶液。这种眼用溶液的pH优选用合适的缓冲体系保持在6.5-7.2。制剂中也可以含有常规的可药用的防腐剂、稳定剂和表面活性剂。
可以在本发明药物组合物中使用的优选的防腐剂包括但不限于苯扎氯铵、三氯叔丁醇、硫柳汞、醋酸苯汞和硝酸苯汞。优选的表面活性剂是例如Tween 80。类似地,在本发明的眼用制剂中可以使用各式各样优选的载体。这些载体包括但不限于聚乙烯醇、聚乙烯吡咯烷酮、羟丙基甲基纤维素、泊洛沙姆、羧甲基纤维素、羟乙基纤维素和纯化的水。
在需要或方便时,可以加入渗透压调节剂。这包括但不限于盐类,特别是氯化钠、氯化钾、山梨醇和甘油,或任何其它合适的可眼用的渗透压调节剂。
可以使用各种各样的缓冲剂和调节pH的方法,只要所形成的制剂是可眼用的。因此,缓冲剂包括醋酸盐缓冲剂、柠檬酸盐缓冲剂、磷酸盐缓冲剂和硼酸盐缓冲剂。如果需要,可以使用酸或碱调节这些制剂的pH。
类似地,可用于本发明的眼用抗氧化剂包括但不限于:焦亚硫酸钠、硫代硫酸钠、乙酰半胱氨酸、丁羟苯甲醚和丁羟甲苯。
可以包含在眼用制剂中的其它赋形剂组分是整合剂。优选的螯合剂是依地酸二钠,但也可以用其它螯合剂代替它或与其联合使用。
各组分通常按以下数量使用:
组分 数量(%w/v)
活性组分 约0.001-5
防腐剂 0-0.10
载体 0-40
渗透压调节剂 1-10
缓冲剂 0.01-10
pH调节剂 适量pH4.5-7.5
抗氧化剂 根据需要
表面活性剂 根据需要
纯化水 按需要加至100%
本发明活性化合物的实际剂量取决于具体的化合物和要治疗的病症;适当剂量的选择是熟练技术人员完全了解的。
本发明的眼用制剂被方便地包装成适合计量施用的形式,例如包装在配有滴管的容器内,以方便对眼睛施用。适合逐滴施用的容器通常由合适的惰性和无毒的塑料制成,一般装有约0.5-15mL溶液。
通过总结在图1和图2的反应示意图中的以下非限制性实施例对本发明作进一步的说明,其中化合物在实施例和图中采用相同的标识。
实施例1
环丁烷羧酸乙酯(1)
所述化合物由Aldrich Chemical Co.(P.O.Box 2060,Milwaukee,WI 53201,USA)购得。
实施例2
1-(1-羟基-1-噻吩-2-基甲基)环丁烷羧酸乙酯(2)
向酯1(0.50g,3.9mmol)在THF(6mL)中的-78℃溶液加入二异丙基氨基化锂-(THF)合物(在庚烷/THF/乙苯中的2.0M溶液,1.95mL,3.90mmol)。搅拌30分钟后加入2-噻吩甲醛(667mg,5.95mmol),将混合物搅拌3小时。用TLC分析判断反应完全后,加入NH4Cl饱和水溶液,将反应混合物慢慢温热至23℃。蒸除THF,反应混合物用CH2Cl2萃取2次。合并的有机层用盐水洗,干燥(Na2SO4),过滤并减压浓缩。残余物用快速柱色谱(FCC)法纯化(硅胶,100%己烷后用9∶1己烷/EtOAc),得到上述化合物2。
实施例3
1-噻吩-2-基甲基环丁烷羧酸乙酯(3)
在0℃下向CH3CN(10mL)中加入三甲基碘硅烷(20g,100mmol),将混合物搅拌5分钟。缓慢地加入醇2(5g,20mmol)在CH3CN(10mL)中的溶液,同时保持温度为4-10℃,将反应混合物温热至23℃。在23℃搅拌2小时后,经TLC分析判断反应完全。将混合物倒入0℃的3N NaOH中,加入EtOAc。分离出有机层,用盐水洗,干燥(Na2SO4),过滤并减压浓缩。FCC(硅胶,1∶1己烷/CH2Cl2)得出2.3g上述酯3。
实施例4
(1-噻吩-2-基甲基环丁基)甲醇(4)
在0℃下向酯3(2.3g,10mmol)的Et2O(20mL)溶液中加入硼氢化锂(435mg,20mmol)。搅拌5分钟后,逐滴加入MeOH(640mg,20mmol),在0℃继续搅拌,直至停止起泡。将混合物温热至23℃,再搅拌1小时,此时将混合物倒入3H NaOH中,再搅拌0.5小时。分离出有机层,用盐水洗,干燥(Na2SO4),过滤,减压浓缩。粗制的醇4用FCC(硅胶,1∶1己烷/CH2Cl2)纯化。
实施例5
1-噻吩-2-基甲基环丁烷甲醛(5)
在23℃下将草酰氯(50mL,0.10mmol)加到CH2Cl2(150mL)中,冷却至-78℃。向该混合物中逐滴加入DMSO(16g,0.20mmol),继续搅拌15分钟。然后逐滴加入醇4(7.9g,0.041mmol)的CH2Cl2(50ml)溶液,接着加入Et3N(44g,0.44mmol),将混合物温热至23℃。1小时后,将该混合物倒入NaHCO3饱和水溶液中,分离出有机层。水层用CH2Cl2(2x)萃取,合并的有机相用盐水洗,干燥(Na2SO4),减压浓缩,用FCC纯化(硅胶,100%己烷之后用2∶1己烷/CH2Cl2),得到上述的醛5。
实施例6
1-(1-噻吩-2-基甲基环丁基)丁-2-炔-1-醇(6)
将溴化丙基镁(360mL在THF中的0.5M溶液,0.180mmol)逐滴加到醛5(7.0g,36mmol)在THF(200mL)中的溶液,同时将混合物保持在环境温度。在23℃搅拌下3小时后,将反应混合物倒入NH4Cl饱和溶液中,用Et2O萃取。分离出有机相,用NaHCO3饱和水溶液和盐水洗,然后干燥(Na2SO4),减压浓缩。FCC(硅胶,100%己烷,然后用1∶1己烷/CH2Cl2)纯化后得到6.2g上述的炔6。
实施例7
1-(1-噻吩-2-基甲基环丁基)丁-3-炔-1-醇(7)
在干燥的圆底烧瓶中装入氢化钾(5.5g,48mmol;在油中的35%重量份散体),通过己烷淋洗(3x)除去油。向该混合物中加入氨基丙酰胺(39mL),搅拌至停止出泡。然后将混合物冷却至0℃,加入炔6(2g,9.1mmol),将反应混合物在23℃搅拌1小时。用MeOH(2mL)和水猝灭反应。反应混合物用乙醚萃取3次,有机层用1N HCl和盐水洗,干燥(Na2SO4),减压浓缩。FCC(硅胶,1∶1己烷/CH2Cl2)得到570mg上述炔7。
实施例8
叔丁基二甲基[1[(1-噻吩-2-基甲基环丁基)丁-3-炔氧基]硅烷(8)
向冷却到0℃的炔7(200mg,0.9mmol)、CH2Cl2(5mL)及三乙胺(275mg,2.72mmol)的溶液逐滴加入三氟甲磺酸叔丁基二甲基甲硅烷基酯(360mg,1.36mmol)。在0℃下搅拌5分钟后,将混合物温热至23℃,再搅拌1小时。然后用NaHCO3饱和水溶液猝灭反应,用CH2Cl2萃取2次。合并的有机相用1N盐酸、NaHCO3饱和水溶液和盐水洗,然后干燥(Na2SO4)、过滤和减压蒸发。FCC(硅胶,100%己烷)得到695mg上述化合物8。
实施例9
叔丁基-[(E)-4-碘代-1-(1-噻吩-2-基甲基环丁基)丁-3-烯氧基]二甲基硅烷(9)
在23℃下向炔8(263mg,0.786mmol)在CH2Cl2(5mL)中的溶液加入Cp2ZrHCl(304mg,1.18mmol),保持搅拌20分钟。向该混合物中加入N-碘代琥珀酰亚胺(247mg,1.18mmol),再继续搅拌30分。将混合物减压浓缩,用己烷/Et2O稀释,过滤并减压浓缩。FCC(硅胶,100%己烷)得到360mg上述化合物9。
实施例10
7-[(R)-3-(叔丁基二甲基硅氧烷基)-5-氧代环戊-1-烯基]庚酸甲酯(10)
上述化合物由Nissan Chemical Industries,LTD,Tokyo 101-0054.Japan购得。
实施例11
7-{(1R,2R,3R)-2-[(E)-(叔丁基二甲基硅氧烷基)-(1-噻吩-2-基甲基环丁基)丁-1-烯基]-3-[(二甲基乙基)二甲基硅氧烷基]-5-氧代环戊基}庚酸甲酯(11)
向乙烯基碘9(120mg,0.259mmol)在乙醚(1.5mL)中的-78℃溶液中加入叔丁基锂(0.35mL的1.5M THF溶液,0.52mmol)。在-78℃搅拌30分钟后,加入2-噻吩基(氰基)铜锂(1.14mL,0.285mmol),再继续搅拌30分钟。反应混合物随后用烯酮10(91.6mg,0.259mmol)的乙醚(1mL)溶液处理。几分钟后,反应混合物已固化,加入0.5mL Et2O。将反应混合物在-78℃搅拌1小时,倒入NH4Cl饱和水溶液中,用EtOAc萃取3次。合并的有机相用盐水洗,过滤并减压浓缩。FCC(硅胶,100%己烷;9∶1己烷/EtOAc)得到63mg上述化合物11。
实施例12
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-噻吩-2-基甲基环丁基)丁-1-烯基]-5-氧代环戊基}庚酸甲酯(12H)
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-噻吩-2-基甲基环丁基)丁-1-烯基]-5-氧代环戊基}庚酸甲酯(12L)
在23℃下向二-TBS醚11(63mg,0.912mmol)在CH3CN(3mL)中的溶液加入氟化氢-吡啶(0.091mL)。搅拌3小时后,用Na2CO3饱和水溶液猝灭反应,用EtOAc萃取3次。合并的有机相用1NHCl、NaHCO3饱和水溶液及盐水洗,然后干燥(Na2SO4),过渡并减压蒸发。FCC(硅胶,3∶2的己烷/EtOAc,然后用1∶1的己烷/EtOAc)得到较高Rf的二醇(10mg)和较低Rf的二醇(30mg),后文分别称为标题化合物12H和12L。
实施例13H
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-噻吩-2-基甲基环丁基)丁-1-烯基]-5-氧代环戊基}庚酸(13H)
甲酯12H(4.8mg,10.4mmol)和PLE(0.134mmol,45mmol)在磷酸盐缓冲液(2mL,pH7.20中于23℃搅拌16小时以上。待反应完全后,将混合物过滤,水相用EtOAc萃取3次。合并的有机相用盐水洗,用硫酸钠干燥,过滤并减压浓缩。FCC(硅胶,1∶1己烷/乙酸乙酯;乙酸乙酯)得到以上的酸13H。
实施例13L
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-噻吩-2-基甲基环丁基)丁-1-烯基]-5-氧代环戊基}庚酸(13L)
甲酯12L按照实施例13H的方法反应,得到上述化合物。
实施例14
(Z)-7-[(R)-3-(叔丁基二甲基硅氧烷基)-5-氧代环戊-1-烯基]庚-5-烯酸甲酯(14)
以上化合物由Nissan Chemical Industries,LTD,Tokyo 101-0054Japan购得。
实施例15
(Z)-7-{(1R,2R,3R)-2-[(E)-(叔丁基二甲基硅氧烷基)-(1-噻吩-2-基甲基环丁基)丁-1-烯基]-3-[(二甲基乙基)二甲基硅氧烷基]-5-氧代环戊基}庚-5-烯酸甲酯(15)。
以上实施例14的化合物按照实施例11的方法反应,得到以上的标题化合物。
实施例16
(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-噻吩-2-基甲基环丁基)丁-1-烯基]-5-氧代环戊基}庚-5-烯酸甲酯(16H)
(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-噻吩-2-基甲基环丁基)丁-1-烯基]-5-氧代环戊基}庚-5-烯酸甲酯(16L)
实施例15的化合物按照实施例12的方法反应,得到Rf较高的二醇(600mg)和Rf较低的二醇(6.0mg),以后分别称为16H和16L。
实施例17H
(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-噻吩-2-基甲基环丁基)丁-1-烯基]-5-氧代环戊基}庚-5-烯酸(17H)
实施例16的化合物16H按照实施例13H的方法反应,得到以上的标题化合物。
实施例17L
(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-噻吩-2-基甲基环丁基)丁-1-烯基]-5-氧代环戊基}庚-5-烯酸(17L)
实施例16的化合物16L按照实施例13H的方法反应,得到以上标题化合物。
实施例18
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氯环戊基}庚-5-烯酸甲酯(18H和18L)。
用合适的氯衍生物代替(Z)-7-[(R)-3-(叔丁基二甲基硅氧烷基)-5-氧代环戊-1-烯基]庚-5-烯酸甲酯14,和用合适的氯噻吩基衍生物代替2-噻吩基(氰基)铜锂,重复实施例14至实施例16,得到的产物经分离后得到Rf较高的二醇和Rf较低的二醇,分别称为18H和18L。
实施例19H
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氯环戊基}庚-5-烯酸(19H)
实施例18H的化合物按照实施例13H的方法反应,得到标题化合物。
实施例19L
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氯环戊基}庚-5-烯酸(19L)
实施例18L化合物按照实施例13L的方法反应,得到标题化合物。
实施例20
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氟环戊基}庚-5-烯酸甲酯(20H和20L)。
用合适的氟衍生物代替(Z)-7-[(R)-3-(叔丁基二甲基硅氧烷基)-5-氧代环戊-1-烯基]庚-5-烯酸甲酯14,并用合适的氯噻吩基衍生物代替2-噻吩基(氰基)铜锂,重复实施例14至16,得到的产物分离后得到Rf较高的二醇和Rf较低的二醇,分别称为20H和20L。
实施例21H
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氟环戊基}庚-5-烯酸(21H)
实施例20H的化合物按照实施例13H的方法反应,得到标题化合物。
实施例21L
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氟环戊基}庚-5-烯酸(21L)
实施例20L的化合物按照实施例13L的方法反应,得到标题化合物。
实施例22
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]环戊烯基}庚-5-烯酸甲酯
用合适的降酮基衍生物代替(Z)-7-[(R)-3-(叔丁基二甲基硅氧烷基)-5-氧代环戊-1-烯基]庚-5-烯酸甲酯14,并用合适的氯噻吩基衍生物代替2-噻吩基(氰基)铜锂,重复实施例14至16,得到的产物经分离后得到Rf较高的二醇和Rf较低的二醇,分别称为22H和22L。
实施例23H
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]环戊烯基}庚-5-烯酸(23H)
实施例22H的化合物按照实施例13H的方法反应,得到标题化合物。
实施例23L7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]环戊烯基}庚-5-烯酸(23L)
实施例22L的化合物按照实施例13L的方法反应,得到标题化合物。
放射性配体结合性
重组EP2受体;将短暂转染子COS-7细胞按照制造商的程序说明用Lipofectin(脂转染试剂,Gibco-BRL Life Technologies,Gaitherburg,MD,U.S.A)短暂转染。对于结合性研究,将2×106个细胞于转染前24小时置于150nm培养皿的平板上。各平板用50μg质粒DNA和50μLLipofectin转染。在转染后48小时收集细胞并制备膜,在-80℃下冷冻直至使用。
将质粒膜制品在室温下解冻并以500μL体积内最终浓度为1mg/mL的条件使用。按双份样品测定[3H]-PGE2(比活性180Cimmol-1)的结合度,重复实验3次。在25℃下温育60分钟,通过加入4mL冰冷的50μM Tris-HCL终止实验,随后经Whatman GF/B滤膜快速过滤,并再用4mL洗液在细胞收取器(Brandel)中洗3次。用最终浓度为5μM的[3H]-PGE2进行竞争性研究,用10μM的各个未标记的前列腺素类测定非特异结合。
试验了以上一些化合物在上述重组人EP2受体试验中的活性,结果列在下面表1中。注意实施例20和21分别是实施例20H和20L及21H和21L的未分离的混合物。
EP2活性表明,本发明的化合物可用于治疗哮喘、痛经以及青光眼和降低眼内压。
其它可能的治疗用途是骨质疏松、便秘、肾病、性功能障碍、秃发、糖尿病、癌症和免疫调节障碍。
本发明化合物还可用于治疗各种病理生理学疾病,包括急性心肌梗死、血管血栓形成、高血压、肺高血压、缺血性心脏病、充血性心力衰竭和心绞痛,在这种情形化合物可以采用能实现血管扩张并从而缓解疾病症状的任何方式给药。例如可以通过口服、经皮、非肠道、皮下、静脉内、肌内、腹腔或颊含等方式给药。
本发明化合物可以配制成在合适的基料(例如白凡士林、矿物油和凡士林与羊毛酯醇)中含约0.10-10%活性组分的软膏。其它合适的基料对于本领域技术人员将是显而易见的。
本发明的药物制剂是按照本身已知的方式制备,例如,将均为水溶性或可悬浮的本发明化合物用常规的溶解或悬浮方法制备。对于在治疗所述的其它病理生理障碍中给药,可以口服使用的药物制剂包括由明胶制成的推合式胶囊,以及由明胶和一种增塑剂如甘油或山梨醇制成的密封的软胶囊。推合式胶囊可以装有液体形式的活性化合物,该化合物可以与填料(例如乳糖)、粘合剂(如淀粉)和/或润滑剂(如滑石或硬脂酸镁)以及任选存在的稳定剂混合。在软胶囊中,活性化合物优选溶解或悬浮于合适的液体如缓冲盐溶液中。此外,还可以加入稳定剂。
除了液体形式,例如在明胶胶囊或其它合适的载体中,药物制剂还可以含有合适的赋形剂以方便将活性化合物加工成能够药学上使用的制剂。例如,用于口服的药物制剂可以通过将活性化合物的溶液粘附在固体载体上得到,如果愿意或者需要,在加入合适的辅剂之后,可以任选地将形成的混合物研磨并将该颗粒混合物加工得到片剂或糖衣药丸的核心。
合适的赋形剂特别是填料例如糖(如乳糖或蔗糖)、甘露醇或山梨醇,纤维素制品和/或磷酸钙(例如磷酸三钙或磷酸氢钙),以及粘合剂,例如淀粉(如玉米淀粉、小麦淀粉、米淀粉、土豆淀粉)、明胶、黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮。如果需要,可以加入崩解剂,例如上述的淀粉及羧甲基淀粉、交联的聚乙烯吡咯烷酮、琼脂或藻酸或其盐,例如藻酯钠。辅助剂尤其是流动调节剂和润滑剂,例如二氧化硅、滑石、硬脂酸或其盐(例如硬脂酸镁或硬脂酸钙)和/或聚乙二醇。糖衣药丸核心配有合适的包衣,如果需要,包衣可以是耐胃酸的。为此,可以使用浓的糖溶液,其中可任选地含有阿拉伯胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、漆溶液和合适的有机溶剂或溶剂混合物。为了得到耐胃酸的包衣,使用合适的纤维素制品如乙酸苯二甲酸纤维素或苯二甲酸羟丙基甲基纤维素。可以在片剂或糖衣丸剂包衣中加入染料或颜料,用于辨识或鉴别活性化合物剂量的组合。
适合静脉内或非肠道给药的制剂包括活性化合物的水溶液。此外,也可以用油质注射悬浮剂形式的活性化合物的悬浮液给药。水基的注射悬浮剂中可以含有提高悬浮液粘度的物质,包括例如羧甲基纤维素钠、山梨醇和/或葡聚糖。悬浮液中还可任选地含有稳定剂。
以上说明详述了可以用来实施本发明的具体方法和组合物,并代表了所考虑的最佳模式。然而,对于本领域的普通技术人员,显然可以用类似的方式制备出具有所要的药理性质的其它化合物,而且所公开的化合物也可以由不同的起始化合物出发经由不同的化学反应得到。类似地,可以制备和使用不同的药物组合物而效果基本相同。因此,不管在正文中的前述说明多么详细,都不应将其看作是对本发明整个范围的限制;相反,本发明的范围只由所附权利要求的法定解释决定。
Claims (31)
2.权利要求1的方法,其中在杂芳基上的取代基是选自C1-C6烷基、OR4、CO2R4、卤素、三氟甲基、COR4、COCF3、SO2NR4、NO2和CN。
5.权利要求4的方法,其中虚线代表双键。
6.权利要求4的方法,其中虚线代表单键。
7.权利要求5的方法,其中R是CO2R4,R4是H。
8.权利要求6的方法,其中R是CO2R4,R4是H。
9.权利要求5的方法,其中R是CO2R4,R4是甲基。
10.权利要求6的方法,其中R是CO2R4,R4是甲基。
11.权利要求4的方法,其中R是CO2R4。
12.权利要求11的方法,其中R4选自H和低级烷基。
13.权利要求4的方法,其中A是C,R5、R6和R7是H。
14.权利要求1的方法,其中X选自氢、氟和氯。
15.权利要求14的方法,其中X是氢。
16.权利要求14的方法,其中X是氟。
17.权利要求14的方法,其中X是氯。
18.权利要求1的方法,其中化合物是7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氯环戊基}庚-5-烯酸甲酯。
19.权利要求1的方法,其中化合物是7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氯环戊基}庚-5-烯酯。
20.权利要求1的方法,其中化合物是(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氟环戊基}庚-5-烯酸甲酯。
21.权利要求1的方法,其中化合物是(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氟环戊基基}庚-5-烯酸。
22.一种眼用溶液,其中含有有效数量的权利要求1定义的式I化合物或其可药用盐和与其混合的一种无毒的可药用液体载体,它们被包装在适合计量施用的容器内。
23.权利要求22的眼用溶液,其中该化合物是式III化合物。
24.一种药物产品,该产品包括一个适合以计量方式分配该容器内容物的容器,和在该容器内的眼用溶液,该溶液含有权利要求1中定义的式I化合物或其可药用盐,和与其混合的一种无毒的可眼用的液体载体。
25.权利要求24的产品,其中该化合物是式III化合物。
27.权利要求26的化合物,其中R是CO2R4。
28.权利要求27的化合物,其中R4是选自H和低级烷基。
29.权利要求28的化合物,其中该化合物用下式表示
30.权利要求29的化合物,其中A是C,R5、R6和R7是H。
31.权利要求30的化合物,其中该化合物是选自:
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氯环戊基}庚-5-烯酸甲酯
7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氯环戊基}庚-5-烯酸
(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氟环戊基}庚-5-烯酸甲酯
(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]-5-氟环戊基}庚-5-烯酸
(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]环戊烯基}庚-5-烯酸甲酯
(Z)-7-{(1R,2R,3R)-3-羟基-2-[(E)-4-羟基-4-(1-(5-氯噻吩-2-基)甲基环丁基)丁-1-烯基]环戊烯基}庚-5-烯酸。
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Families Citing this family (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6875787B2 (en) * | 2003-02-11 | 2005-04-05 | Allergan, Inc. | 10,10-dialkyl prostanoic acid derivatives as agents for lowering intraocular pressure |
US7855226B2 (en) * | 2003-02-11 | 2010-12-21 | Allergan, Inc. | Treatment of inflammatory bowel disease |
GB0329620D0 (en) * | 2003-12-22 | 2004-01-28 | Pharmagene Lab Ltd | EP2 receptor agonists |
US7326732B2 (en) | 2004-02-12 | 2008-02-05 | Pharmagene Laboratories Limited | EP2 receptor agonists |
EP1812017A2 (en) * | 2004-10-21 | 2007-08-01 | Duke University | Ophthamological drugs |
US7091231B2 (en) * | 2004-12-10 | 2006-08-15 | Allergan, Inc. | 12-Aryl prostaglandin analogs |
DK1846354T3 (da) | 2005-01-14 | 2010-08-16 | Allergan Inc | Substituterede cyclopentaner eller cyclopentanoner til behandling af okular hypertensive tilstande |
DK1856042T3 (da) * | 2005-03-10 | 2012-09-17 | Allergan Inc | Substituerede gamma-lactamer som terapeutiske midler |
JP5254007B2 (ja) * | 2005-05-06 | 2013-08-07 | アラーガン インコーポレイテッド | 置換β−ラクタム及び医薬におけるその使用 |
US7674786B2 (en) * | 2005-05-06 | 2010-03-09 | Allergan, Inc. | Therapeutic β-lactams |
US8039507B2 (en) * | 2005-06-29 | 2011-10-18 | Allergan, Inc. | Therapeutic substituted gamma lactams |
AU2006277786B2 (en) | 2005-08-09 | 2012-09-06 | Asterand Uk Acquisition Limited | EP2 receptor agonists |
US7427685B2 (en) | 2005-12-06 | 2008-09-23 | Allergan, Inc. | Therapeutic substituted cyclopentanes |
US7585895B2 (en) * | 2005-12-06 | 2009-09-08 | Allergan, Inc. | Therapeutic substituted cyclopentanes |
US7592364B2 (en) * | 2006-02-28 | 2009-09-22 | Allergan, Inc. | Substituted gamma lactams as therapeutic agents |
AU2007226957B2 (en) * | 2006-03-20 | 2013-08-15 | Allergan, Inc. | Substituted gamma lactams as prostaglandin EP2 agonists |
US20070254920A1 (en) * | 2006-04-26 | 2007-11-01 | Aerie Pharmaceuticals, Inc. | Prodrug derivatives of acids using alcohols with homotopic hydroxy groups and methods for their preparation and use |
US7439372B2 (en) | 2006-05-03 | 2008-10-21 | Allergan, Inc. | Therapeutic compounds |
US20090016981A1 (en) | 2006-05-03 | 2009-01-15 | Allergan, Inc. | Therapeutic compounds |
WO2008021804A2 (en) * | 2006-08-09 | 2008-02-21 | Allergan, Inc. | Therapeutic amides and related compounds |
US7985767B2 (en) * | 2006-09-06 | 2011-07-26 | Allergan, Inc. | Therapeutic amides |
EP1903037A1 (de) * | 2006-09-07 | 2008-03-26 | Bayer Schering Pharma Aktiengesellschaft | 1-(Het)aryl-3-[hetaryl-piperidin-4-yl]-thioharnstoffe als Modulatoren des EP2-Rezeptors |
WO2008073752A2 (en) * | 2006-12-11 | 2008-06-19 | Allergan, Inc. | Cyclobutyl derivatives for the treatment of glaucoma |
US20100011786A1 (en) * | 2006-12-28 | 2010-01-21 | Lg Electronics Inc. | Ice making system and method for ice making of refrigerator |
CA2675632A1 (en) * | 2007-01-22 | 2008-07-31 | Allergan, Inc. | Substituted arylcyclopentenes as therapeutic agents |
ATE511506T1 (de) * | 2007-01-22 | 2011-06-15 | Allergan Inc | Thiopen-derivate als wirkstoffe gegen okulare hypotonie |
BRPI0808377B8 (pt) * | 2007-01-31 | 2021-05-25 | Allergan Inc | composto, composição e uso de um composto |
WO2009065081A2 (en) | 2007-11-14 | 2009-05-22 | Cayman Chemical Company | Prostaglandin e1 and e2 analogs for the treatment of various medical conditions |
US8063033B2 (en) | 2008-01-18 | 2011-11-22 | Allergan, Inc. | Therapeutic beta-lactams |
US7956051B2 (en) * | 2008-01-24 | 2011-06-07 | Allergan, Inc. | Therapeutic amides and related compounds |
US8633310B2 (en) * | 2008-02-19 | 2014-01-21 | Allergan, Inc. | Therapeutic substituted lactams |
WO2009111322A1 (en) * | 2008-03-04 | 2009-09-11 | Allergan, Inc. | Substituted cyclopentanes having prostaglandin activity |
US8202855B2 (en) | 2008-03-04 | 2012-06-19 | Allergan, Inc | Substituted beta-lactams |
US7964596B2 (en) * | 2008-03-07 | 2011-06-21 | Allergan, Inc. | Therapeutic compounds |
US20090233921A1 (en) * | 2008-03-11 | 2009-09-17 | Allergan, Inc. | Therapeutic cyclopentane derivatives |
US7960379B2 (en) * | 2008-03-14 | 2011-06-14 | Allergan, Inc. | Therapeutic compounds |
US7705001B2 (en) * | 2008-03-18 | 2010-04-27 | Allergan, Inc | Therapeutic substituted gamma lactams |
US7732443B2 (en) * | 2008-03-18 | 2010-06-08 | Yariv Donde | Therapeutic substituted cyclopentanes |
US8198318B2 (en) * | 2008-03-18 | 2012-06-12 | Allergen, Inc. | Therapeutic amides |
US7960378B2 (en) * | 2008-03-18 | 2011-06-14 | Allergan, Inc. | Therapeutic compounds |
US7956055B2 (en) * | 2008-03-25 | 2011-06-07 | Allergan, Inc. | Substituted gamma lactams as therapeutic agents |
US7737140B2 (en) * | 2008-04-24 | 2010-06-15 | Allergan, Inc. | Therapeutic compounds |
EP2297084A1 (en) * | 2008-04-24 | 2011-03-23 | Allergan, Inc. | Therapeutic compounds |
BRPI0911347A2 (pt) | 2008-04-24 | 2018-03-20 | Allergan Inc | gama lactamas substituídas como agentes terapêuticos |
US7803798B2 (en) * | 2008-04-24 | 2010-09-28 | Allergan, Inc. | Therapeutic compounds |
BRPI0911543A2 (pt) * | 2008-04-24 | 2015-10-13 | Allergan Inc | arilciclopentenos substituídos como agentes terapêuticos |
EP2291367A1 (en) | 2008-04-24 | 2011-03-09 | Allergan, Inc. | Substituted gamma lactams as therapeutic agents |
CA2722456A1 (en) * | 2008-04-24 | 2009-10-29 | Allergan, Inc. | Substituted arylcyclopentenes as prostaglandin ep2 agonists |
US7964634B2 (en) * | 2008-04-24 | 2011-06-21 | Allergan, Inc. | Therapeutic compounds |
CA2723893A1 (en) * | 2008-05-09 | 2009-11-12 | Allergan, Inc. | Therapeutic n-aryl or n-heteroaryl pyrazolidine and pyrazolidinone derivatives |
US7981887B2 (en) * | 2008-05-09 | 2011-07-19 | Allergan, Inc. | Therapeutic compounds |
KR20110017878A (ko) * | 2008-05-09 | 2011-02-22 | 알러간, 인코포레이티드 | 치료학적인 치환된 티아졸리딘온, 옥사졸리딘온, 및 관련 화합물 |
US8569349B2 (en) * | 2008-05-09 | 2013-10-29 | Allergan, Inc. | Therapeutic compounds |
AU2009244541B2 (en) * | 2008-05-09 | 2014-01-09 | Allergan, Inc. | Therapeutic compounds |
EP2303836A1 (en) * | 2008-05-09 | 2011-04-06 | Allergan, Inc. | Therapeutic cyclopentane derivatives |
WO2009137343A1 (en) | 2008-05-09 | 2009-11-12 | Allergan, Inc. | Therapeutic substituted hydantoins, and related compounds |
AU2009246573B2 (en) * | 2008-05-15 | 2014-04-24 | Allergan, Inc. | Therapeutic substituted cyclopentanes |
WO2009142969A1 (en) * | 2008-05-20 | 2009-11-26 | Allergan, Inc. | Therapeutic lactams |
EP2300412A1 (en) * | 2008-05-27 | 2011-03-30 | Allergan, Inc. | Prostaglandin produgs as hypotensive agents |
US7985765B2 (en) * | 2008-08-20 | 2011-07-26 | Allergan, Inc. | Therapeutic substituted pyrroles |
US20110293549A1 (en) | 2009-02-03 | 2011-12-01 | Athena Cosmetics, Inc. | Composition, method and kit for enhancing hair |
CA2925927C (en) | 2013-09-30 | 2022-09-06 | George Petros Yiannikouros | Novel synthesis routes for prostaglandins and prostaglandin intermediates using metathesis |
US10105488B2 (en) | 2013-12-12 | 2018-10-23 | Medtronic Minimed, Inc. | Predictive infusion device operations and related methods and systems |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5034413A (en) | 1989-07-27 | 1991-07-23 | Allergan, Inc. | Intraocular pressure reducing 9,11-diacyl prostaglandins |
US5028624A (en) | 1989-07-27 | 1991-07-02 | Allergan, Inc. | Intraocular pressure reducing 9,15-diacyl prostaglandins |
CA2021316C (en) | 1989-07-27 | 2000-10-24 | Ming Fai Chan | Intraocular pressure reducing 11-acyl prostaglandins |
US4994274A (en) | 1989-07-27 | 1991-02-19 | Allergan, Inc. | Intraocular pressure reducing 11,15-diacyl prostaglandins and method of using |
EP0825980B1 (en) * | 1995-05-18 | 2001-07-04 | Allergan Sales, Inc. | Cyclopentane heptan(ene)oic acid, 2-heteroarylakenyl derivatives as therapeutic agents for the treatment of ocular hypertension |
JP2001139544A (ja) * | 1999-11-12 | 2001-05-22 | Taisho Pharmaceut Co Ltd | プロスタグランジン誘導体 |
KR20030019628A (ko) * | 2000-07-31 | 2003-03-06 | 오노 야꾸힝 고교 가부시키가이샤 | 프로스타글란딘 유도체를 유효 성분으로 하는 발기부전치료제 |
US6248783B1 (en) * | 2000-09-20 | 2001-06-19 | Allergan Sales, Inc. | Cyclopentane 1-hydroxy alkyl or alkenyl-2-one or 2-hydroxy derivatives as therapeutic agents |
US6376533B1 (en) * | 2000-10-20 | 2002-04-23 | Allergan Sales, Inc. | Omega-cycloalkyl 17-heteroaryl prostaglandin E2 analogs as EP2-receptor agonists |
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2002
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- 2002-10-25 EP EP02791192A patent/EP1442033B1/en not_active Expired - Lifetime
- 2002-10-25 BR BR0213911-1A patent/BR0213911A/pt not_active IP Right Cessation
- 2002-10-25 NZ NZ532519A patent/NZ532519A/en unknown
- 2002-10-25 WO PCT/US2002/034301 patent/WO2003040126A1/en active IP Right Grant
- 2002-10-25 KR KR1020047006769A patent/KR20050039733A/ko not_active Application Discontinuation
- 2002-10-25 DE DE60206408T patent/DE60206408T2/de not_active Expired - Fee Related
- 2002-10-25 CN CNA02826178XA patent/CN1617868A/zh active Pending
- 2002-10-25 CA CA002466517A patent/CA2466517A1/en not_active Abandoned
- 2002-10-25 MX MXPA04004164A patent/MXPA04004164A/es active IP Right Grant
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US7514462B2 (en) | 2009-04-07 |
DE60206408D1 (de) | 2006-02-09 |
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ATE305463T1 (de) | 2005-10-15 |
HK1066801A1 (en) | 2005-04-01 |
WO2003040126A1 (en) | 2003-05-15 |
EP1442033B1 (en) | 2005-09-28 |
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US20040106580A1 (en) | 2004-06-03 |
NZ532519A (en) | 2006-11-30 |
US20070219262A1 (en) | 2007-09-20 |
KR20050039733A (ko) | 2005-04-29 |
ES2246419T3 (es) | 2006-02-16 |
US7022726B2 (en) | 2006-04-04 |
BR0213911A (pt) | 2004-09-28 |
CA2466517A1 (en) | 2003-05-15 |
US20050113338A1 (en) | 2005-05-26 |
DE60206408T2 (de) | 2006-06-22 |
EP1442033A1 (en) | 2004-08-04 |
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